tbuckley/cabot-search huggingface dataset:
P07.07.B INDUCTION AND TARGETING OF DIFFUSE MIDLINE GLIOMA IN A NOVEL HUMAN PONTINE ORGANOID MODEL
Authors: N Bessler, C Ruiz Moreno, A Wezenaar, N Dommann, F Keramati, H C R Ariese, C Honhoff, S de Blank, M Barrera Román, M Alieva, E J Wehrens, A Alemany, H G Stunnenberg, A C Rios
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse Midline Glioma (DMG) is a rare and aggressive pediatric brain cancer with no chance of survival, highlighting a critical need for therapy development. Disease representative models can aid the search for effective treatments, but human preclinical models that reflect the unique developmental features and anatomical environment of DMG, are so far lacking. Latest research on DMG suggest a fetal neurodevelopmental origin with a stem cell-like cellular profile. Here, we developed a novel pontine hindbrain model to create de novo H3K27M DMG and applied it to study early tumorigenesis and immunotherapy response. MATERIAL AND METHODS Timely sequenced morphogens were applied to developing cerebral organoids, to create a new pontine patterned brain organoid model. Bulk sequencing and 3D imaging over a period of 16 weeks were used to determine ideal patterning conditions, confirm the correct brain regionality and reconstruct cellular developmental dynamics. Introducing H3K27M with common pontine mutations P53 and PDGFRA-D842V via electroporation resulted in de novo H3K27M DMG, which subsequently was characterized based on WHO-histopathological criteria and single cell sequencing. Exploiting this new human DMG model, we applied barcode-based genetic lineage tracing paired with single cell sequencing, to delineate tumorigenesis, and anti-GD2 chimeric antigen receptor (CAR) T cell therapy to investigate CAR T cell responses. RESULTS Our novel pontine hindbrain organoid model inherently gives rise to all relevant macroglia and pons-specific neurons, resembling the same developmental dynamics as seen in humans. Moreover, de novo DMG introduced in these pontine organoids strongly resembles patient cancer, including its cellular human-specific heterogeneity and invasive nature, outperforming existing gold standard PDX and cell line models. As a first model for investigating DMG, the applied barcoded lineage-tracing delineates cancerous transforming precursor states and how they contribute to the diverse lineage among known DMG cancer cell populations. Finally, administration of CAR T cells recreates treatment outcomes observed in patients and demonstrates a high level of CAR T cell heterogeneity. CONCLUSION We generated a bona fide DMG pontine hindbrain organoid model, the first human in vitro model for this specific region of the brain. The matching resemblance to patient tumor paired with the relevant healthy brain environment gives this model the potential for new insights into DMG early tumorigenesis and microenvironmental impact, as well as next generation therapy development.
P10.11.A CHARACTERISTICS OF DIFFUSE MIDLINE GLIOMA WITH H3 K27M MUTATION IN ADULTS
Authors: K Tanaka, H Nagashima, S Yamanishi, T Itoh, T Sasayama
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND H3 K27M-mutant diffuse midline gliomas (DMG) occur primarily in children but can also be encountered in adults. Adult H3 K27M-mutant DMG is a still challenging disease with no effective medical therapies. MATERIAL AND METHODS We retrospectively analyzed the characteristics and prognostic factors of 49 adult patients with intracranial midline gliomas treated in Kobe University Hospital from 2006 to 2022. RESULTS The median age at diagnosis in midline gliomas was 50.8 years (range: 17-83 y). All tumors were located in thalamus n=25, brainstem n=10, cerebellum n=14. Isocitrate dehydrogenase 1 (IDH1) and H3 K27M mutation was recognized in 6 and 16 patients, respectively, which was mutually exclusive. In all midline gliomas, the identification of H3 K27M mutation was significantly a poor prognosis factor (median 18.5 months vs 34.2 months, p=0.041). Among IDH1 wild-type midline gliomas, however, H3 K27M-mutant DMG had no worse overall survival (median 18.8 months vs 22.2 months, p=0.805). CONCLUSION H3 K27M-mutant DMG is considered as a distinct WHO Grade 4 regardless of histological features, but the biological properties of H3 K27M mutation is not yet defined in IDH1 wild-type midline gliomas in adults.
P11.61.B TUMOR ASSOCIATED EPILEPSY AND RESTRICTION OF DRIVING PRIVILEGES IN THE FIRST YEAR AFTER BRAIN TUMOR SURGERY
Authors: D D Dimov, S Lazarov, M Simon
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In most countries, the risk of postoperative seizures prompts regulations restricting driving privileges at least temporarily following brain tumor operations. The present study investigated the frequency of epileptic seizures and driving habits in the first year after brain tumor operations in a prospective and a retrospective patient cohort. MATERIAL AND METHODS The authors studied overall 523 patients undergoing surgery for a brain tumor at the authors’ institution (prospective cohort, 09/2021-09/2022: N=313 and retrospective cohort, 01/2020-12/2020: N=210). Clinical data were obtained by reviewing patient charts and through (telephone) interviews. RESULTS The cohort included 160 (30.6%) meningiomas, 135 (25.6%) glioblastomas, 111 (21.2%) metastases and 56 (10.7%) other gliomas. 135/523 (25.8%) presented with seizure(s). At 3 months (excluding early post operative seizures) overall 57 (10.9%; prospective vs. retrospective cohort: 13.2 vs. 8.1%) patients reported seizure(s). The seizure incidence at 1 year was 18.4% (prospective vs. retrospective cohort: 18.7 vs. 18.2%). 22/173 (12.7%) patients reported de-novo seizures at 1 year. Significant predictors of seizures at 1 year included preoperative seizures (p&amp;lt;0.001), an adverse preoperative and postoperative KPI (p=0.038 and p=0.001) as well as postoperative NANO (p&amp;lt;0.001) score and histology (e.g. meningiomas: 7.5%, metastases: 22.0%, glioblastomas: 38.5%, other gliomas: 18.8%; p&amp;lt;0.001). 219/318 (69.9%) assessable patients were not driving in 3 months. Reasons included no driver’s license (6.3%), death (7.9%), neurological deficits (38.4%), epilepsy (9.0%), and personal choice (12.9%). 91.3% of glioblastoma patients did not drive in 3 months (cf. metastases: 77.8%, other gliomas. 72.4%, meningiomas: 43.8%; p&amp;lt;0.001). CONCLUSION We documented a high incidence of postoperative seizures and potential risk factors in patients following brain tumor surgery. Our figures support postoperative restriction of driving privileges even in seizure-naive patients (12.7% de-novo seizures at 1 year). Of note, epilepsy was the reason for not driving after surgery for a brain tumor only in 9.0%.
P10.32.B SCREENING FOR OPTIMAL MULTI-TARGET DRUG COMBINATIONS TARGETING THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA
Authors: A Their, C Baltira, K Rozing, J H Beijnen, M C de Gooijer, O van Tellingen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is one of the most malignant adult brain tumors, with a median survival of only 14 months. The lack of efficient therapies so far can be traced back to issues such as resistance to treatments leading to relapses, novel drugs being unable to penetrate the blood-brain barrier (BBB) and focus on monotherapy approaches in a highly heterogeneous disease. Characterization of the genomic landscape of GBM has revealed that three major signaling pathways are co-abrogated in the majority of patients. We have previously shown proof-of-concept that targeting these pathways (PI3K-mTOR-AKT, MAPK and CDK4/6-RB) using a multi-target combination therapy (MTCT) is a promising way to treat GBM. By looking into a panel of drugs, we are screening for alternative MTCT combinations to identify those most suitable for clinical translation. MATERIAL AND METHODS From a panel of drugs targeting one these three pathways, we compare each drug's single-agent properties to various combinations. The synergy of the drugs is scored based on proliferation and target inhibition effects. We will establish if candidate drugs are an ABC transporter substrate with transwell assays and how well the drugs can cross the BBB in vivo using ABC transporter knock-out mouse models. Promising MTCT combinations will be further studied using in vivo orthotopic GBM models. RESULTS We have identified several MTCT combinations that have synergistic effects on target inhibition and cell proliferation. Transwell assays indicate that multiple drugs are to some degree ABC transporter substrates, which might affect the brain penetration of the compounds. Nonetheless, we could identify several candidate drugs targeting the PI3K or MAPK pathway that are relatively weak substrates and for which brain entry is relatively unimpeded. In contrast, finding a candidate with favorable pharmacological properties among the available CDK4/6-RB pathway inhibitors has proven to be more challenging. CONCLUSION Our results indicate that using an MTCT approach might be promising for treating GBM. Further research is being conducted to find the best possible MTCT combination that can access the tumor through the BBB at sufficient levels to exert its pharmacodynamic effects.
P20.11.A TEMPORAL MUSCLE THICKNESS AS PROGNOSTIC MARKER IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA - A VALIDATION STUDY
Authors: M van der Meulen, R Gahrmann, B van der Holt, J K Doorduijn, S Issa, J E C Bromberg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare, aggressive diffuse large B-cell lymphoma, confined to the central nervous system. Age and performance status are validated prognostic variables in PCNSL. Frailty may also be a factor but is not easily quantified. Temporal muscle thickness (TMT), as parameter of sarcopenia, is believed to reflect frailty, is easily measurable and may be a valuable additional prognostic factor: mean TMT has been described as an independent prognostic factor in PCNSL patients. This study aims to validate these results in a prospective cohort. MATERIAL AND METHODS All patients from a large phase III trial (HOVON 105/ALLG NHL 24; EudraCT 2009-014722-42) of whom baseline axial T1 weighted magnetic resonance images (MRI) were available were included. Sarcopenia is defined as a mean TMT &amp;lt;6.3mm for men and &amp;lt;5.2mm for women, measured on axial T1-weighted MRI. The TMT was measured by a radiologist (RG) with and a neurologist (MvdM) without correction for angulation of images. Sarcopenia, together with known other prognostic factors were analyzed in a Cox-regression analysis for progression-free (PFS) and overall survival (OS) for both investigators. RESULTS TMT measurements were possible in 164/199 trial patients. The median mean TMT was 7.62mm (IQR: 6.58-9.00; measured by RG) and 5.94mm (IQR: 5.09-7.01; measured by MvdM). The mean TMT was not significantly different between those who used dexamethasone, and those who did not. Sarcopenia was present in 75 patients (46%), measured by MvdM without correction for angulation of the images and in 21 patients (13%), measured by RG with correction for angulation of the images. In univariate analyses, age (&amp;gt;60 years-old) and baseline Mini-Mental State Examination-score &amp;lt;27 were significantly associated with adverse PFS and OS. In multivariate analyses, only age remained as independent prognostic factor for adverse PFS and OS. Sarcopenia, as measured by either of the investigators, was not associated with survival. For measurements by RG, presumed to be most accurate, the Hazard Ratio (95% confidence interval) was 0.68 (0.33-1.40), p=0.30 for PFS, and HR (95% CI): 0.97 (0.42-2.20), p=0.93 for OS in the multivariate analysis. CONCLUSION There was a low interobserver agreement between a neurologist and a radiologist regarding TMT measurements, which questions the use of this parameter in daily practice by non-radiologists. Sarcopenia, based on the mean TMT, was not a prognostic factor in PCNSL patients for PFS and OS. The small number of patients with sarcopenia in this series may have influenced results.
P10.35.A CDK12/CDK13 INHIBITION DISRUPTS A TRANSCRIPTIONAL PROGRAM CRITICAL FOR GLIOBLASTOMA SURVIVAL
Authors: D P Pandey
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most prevalent and aggressive malignant tumor of the central nervous system. Aberrant transcriptional programs are key to development and maintenance of cancer cells, and these can be exploited to target a specific cancer. Thus, targeting the transcriptional addiction specific for gliomas could offer a large therapeutic potential. METHODS A panel of patient-derived primary glioma stem cell (GSC) lines and glioblastoma organoids (GBO) were used to investigate the effect of transcriptional cyclin-dependent kinase (tCDK) inhibitors using a range of survival assays. A CRISPR/CAS9-based competition assay was applied to study the effect of genetic ablation of individual tCDKs. CUT&amp;RUN was utilized to generate the genome-wide maps of the total RNA polymerase II (RNAPII) and phosphorylated species, and SLAM-seq was used to identify changes in steady-state and nascent transcriptome. Cell cycle analyses were done using EdU incorporation to mark S-phase cells. RESULTS We show that pharmacological inhibition or genetic ablation of the tCDKs, CDK12 and CDK13, markedly reduces the in vitro proliferation of GSCs and of ex vivo glioblastoma organoids as well as migratory capacity of GSCs. Using a xenograft mouse model, we demonstrate that CDK12/13 inhibition reduces tumor growth in vivo, which compares favorably with the existing chemotherapeutic treatments. Mechanistically, inhibition of CDK12/CDK13 leads to a genome-wide abrogation of RNAPII C-terminal Domain (CTD) phosphorylation, which in turn disrupts transcription and cell cycle progression in glioblastoma cells. CONCLUSION s CDK12/CDK13 inhibition may have a large therapeutic potential for glioblastoma treatment, both alone and in combination.
P11.41.B PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM: CASE STUDY REPORTS
Authors: C Guo, Q Yang, J Li, S Wu, X Cao, M Deng, X Du, J Bacha, S Kanekal, C Kwan, G Johnson, R Schwartz, J Langlands, D Brown, Z Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. MATERIAL AND METHODS A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM following surgical resection. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. RESULTS A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. At study completion, the median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Here we report on two patient cases. The first, a 32-yo woman, WHO Gr. 4 GBM (MGMT unmethylated), who received conventional radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 13 cycles of VAL-083. This patient is tumor free suvival more than 4 years till last follow-up (Mar 2023 ). The second, a 49-yo man, WHO Gr. 4 GBM (MGMT unmethylated), who received radiotherapy with concurrent chemotherapy with VAL-083 followed by adjuvant VAL-083, for a total of 12 cycles of VAL-083. Two years after initial treatment with VAL-083 was discontinued, a new lesion was found, and the patient had a second resection, which revealed WHO Gr. 3 astrocytoma. The patient was re-treated with VAL-083,and was stable till last follow-up(Mar 2023). CONCLUSION The results from the study and these patient cases, support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
P14.05.B 2-HYDROXYGLUTARATE IN CEREBROSPINAL FLUID AS A MONITORING BIOMARKER FOR IDH-MUTANT GLIOMAS
Authors: C Riviere-Cazaux, J Lacey, L Carlstrom, W Laxen, A Munoz-Casabella, M Hoplin, S Ikram, A bin Zubair, K Andersen, A Warrington, P Decker, T Kaufmann, J Campian, J Eckel-Passow, S Kizilbash, S Tortorelli, T Burns
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas, no study has evaluated the ability of CSF D-2-HG to quantitatively monitor tumor burden and therapeutic response. Toward this goal, we are routinely obtaining CSF samples from patients prior to, during, and after treatment via intra-operative collection and CSF-access devices. MATERIAL AND METHODS Patients were enrolled into our Ommaya reservoir study (NCT04692337), which enables longitudinal access to CSF. The catheter for the implanted reservoir was placed within the surgical resection cavity following a standard-of-care resection. Intra-operatively collected CSF samples were also biobanked through Mayo Clinic’s Neuro-Oncology biorepository. CSF samples were also acquired via clinically indicated ventriculoperitoneal shunts (VP shunts) or external ventricular drains via our ongoing CSF biomarkers study (NCT04692324). D-and-L-2-HG were assayed from each CSF sample via gas chromatography-mass spectrometry (GC-MS) at Mayo Clinic’s Biochemical Genetics Laboratory. RESULTS CSF was collected prior to and after resection in patients via Ommaya reservoirs or VP shunts, all of whom underwent near gross total resections (&amp;gt;95% of tumor volume). D-2-HG and the D/L ratio fell on average by 57.9% (range: 15.1%-98.6%) and 68.8% (range: 49.3%-98.9%), respectively, following resection. In one patient with a largely intraventricular grade 4 IDH-mutant astrocytoma, D-and-L-2-HG fell by 99.1% and 99.3% by post-operative day 2, consistent with the impact of ventricular contact on baseline CSF D-2-HG levels. In patients for whom CSF was collected throughout chemoradiation, with or without immunotherapy, D-2-HG and the D/L ratio continued to decrease over time, despite concern for pseudoprogression versus progression on imaging. CONCLUSION Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas. Work is ongoing to evaluate the reproducibility of these findings in a larger cohort of patients with low or high-grade gliomas, in addition to the impact of tumor recurrence on 2-HG. Future studies will evaluate the impact of IDH inhibitors and other experimental therapies on CSF 2-HG levels for pharmacodynamic monitoring of treatment response.
P11.58.A CARDIOVASCULAR EVENTS AND VENOUS THROMBOEMBOLISM AFTER PRIMARY MALIGNANT AND NON-MALIGNANT BRAIN TUMOUR DIAGNOSIS: A POPULATION MATCHED COHORT STUDY IN WALES (UNITED KINGDOM)
Authors: M T C Poon, P M Brennan, K Jin, C L M Sudlow, J D Figueroa
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the distribution of risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities. MATERIAL AND METHODS Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥18 years in the primary care database with first diagnosis of malignant and non-malignant brain tumour identified in the cancer registry in 2000-2014, and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any tumour diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour and follow-up period. RESULTS There were 2,869 and 3,931 people diagnosed with malignant and non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12-28.88) and stroke (HR 3.32, 2.44-4.53). Risks of VTE (HR 2.20, 1.52-3.18) and stroke (HR 1.45, 1.00-2.10) remained to be higher than controls for those surviving one year. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73-5.06), stroke (HR 4.06, 3.35-4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26-3.48) within the first year of diagnosis compared with their controls. CONCLUSION The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour.